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Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the [sup.125]I galanin--binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target. galanin | seizure | G protein-coupled receptor | status epilepticus doi/ 10.1073/pnas.1008986107

The past decades have brought several advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs (AEDs), more than one-third of patients are resistant to pharmacological treatment. Furthermore, current AEDs do not prevent the development and progression of epilepsy. Thus, there is an urgent need to develop new therapies for AED-resistant patients, for prevention of epilepsy in patients at risk and for disease modification. Cell replacement and gene therapies have been proposed to offer potential approaches for improvements in therapy, but are such approaches really more promising than new pharmacological strategies? Here we critically review and discuss data from epilepsy models and human tissue studies indicating that cell and gene therapies might provide alternative therapeutic approaches for AED-resistant focal epilepsies and might have antiepileptogenic or disease-modifying potential. However, several crucial issues remain to be resolved to develop cell and gene therapies into effective and safe therapies.

Clinical data demonstrate that certain antiepileptic drugs including carbamazepine (CBZ) decrease serum biotin concentration 45-50% and increase urine and serum organic acids, which is suggestive of reduced function of biotin-dependent enzymes. However, little is known about biotin-dependent enzyme function at the tissue level in patients undergoing long-term CBZ treatment. We recently established that dietary CBZ administration to rats increases brain lactate and also decreases specific enzymatic activity and the relative abundance of hepatic biotinylated pyruvate carboxylase (PC). To examine the mechanism of altered activity and abundance of biotinylated PC, the effect of orally administered CBZ on hepatic PC protein and mRNA expression was examined in rats consuming a physiologically relevant level of dietary biotin (0.06 mg/kg). Rats were fed 0 or 3.4 g CBZ/kg diet for 28 d, a dose designed to achieve clinically relevant serum CBZ concentrations. Hepatic biotinylated PC and PC activity were significantly reduced by ~43 and 30%, respectively, in the drug-treated group. Liver PC protein expression and mRNA were ~43 and 35% lower, respectively, in the drug-treated group than in controls. Brain biotinylated PC was significantly lower (29%), whereas specific enzymatic activity was 175% higher in rats consuming the 3.4 g CBZ/kg diet. Brain, but not serum, lactate was significantly higher in rats consuming CBZ. Taken together, the lower PC protein and mRNA expression provide a plausible biochemical mechanism to explain the decreased abundance of biotinylated hepatic PC observed in previous studies. KEY WORDS: * carbamazepine * biotin * rats * antiepileptic drug * pyruvate carboxylase

The effect of dietary antiepileptic drug administration on the metabolism and function of the water-soluble vitamin biotin was analyzed in a physiologically relevant rat model of biotin nutriture. Administration of carbamazepine (CBZ) in semipurified rat diet at 1.5 and 2.9 g/kg for 19 d did not reduce growth rate or food intake. After this dietary treatment, brain lactic acid and ammonia concentrations were significantly elevated, but no changes in these metabolites occurred in the liver. Urinary biotin excretion was altered and the concentrations of biotin sulfoxides and biocytin in the serum were elevated. Brain biotin was unaffected, but concentrations of bisnorbiotin and biocytin were significantly reduced by dietary administration of CBZ. The relative abundance of hepatic acetyl CoA carboxylase 1 and 2, pyruvate carboxylase (PC), methylcrotonyl CoA carboxylase and propionyl CoA carboxylase was significantly reduced by CBZ, whereas the relative abundance of biotinylated PC was significantly reduced in the brain. In agreement with the carboxylase abundance data, the activity of hepatic PC was significantly reduced in rats consuming CBZ-containing diets. These data demonstrate that administration of the antiepileptic medication CBZ, even with food, reduces the abundance and function of biotin-dependent enzymes in the liver and brain, partially accounting for the metabolic alterations, including organic acidemia, that are observed clinically. KEY WORDS: * biotin * antiepileptic drug * carbamazepine * carboxylase * rats

The finding of decreased thyroid hormone levels in people taking anticonvulsants appears to be an artifact of the test used to measure the hormone levels. Researchers took blood samples from 9 people taking phenytoin and 10 people taking carbamazepine. All 19 had no history of thyroid disease. Adding therapeutic concentrations of the drugs to the blood samples caused total T4 thyroid hormone to drop significantly, but free T4 hormone increased substantially when measured by an assay that uses undiluted blood. This increase in free T4 was not seen when the hormone was measured using an assay that dilutes the blood. In fact, free T4 levels dropped. These drugs displace T4 from T4-binding proteins. This would tend to raise free T4 levels. However, when blood samples are diluted, the drug concentration drops substantially and no longer displaces T4. Physicians should monitor TSH levels in these patients, since TSH levels are usually normal., Objective. - To address the paradox that phenytoin- and carbamazepine-treated patients have decreased serum free thyroxine ([T.sub.4]) and triiodothyronine ([T.sub.3]) concentrations but appear clinically euthyroid and have normal serum thyroid-stimulating hormone (TSH) concentrations. Design. - In vitro studies comparing measurements of total arid free [T.sub.4] and [T.sub.3] by ultrafiltration assay (undiluted serum) and a commercial free [T.sub.4] estimate kit in control serum samples or serum samples containing added therapeutic levels of phenytoin or carbamazepine. These measurements were made in serum samples diluted 1:5 with either identical serum or phosphate buffer, pH 7.4, and in serum samples from patients with seizure disorders who were treated with phenytoin or carbamazepine. Setting. - A 650-bed teaching hospital. Patients. - Selected patents (n=19) who were in good health except for seizure disorder, with stable anticonvulsant drug levels in the upper had of the therapeutic range, and were not taking any other drugs that could affect thyroid parameters. Main Outcome Measure. - Serum concentrations of free [T.sub.4] and free [T.sub.3] in patients taking phenytoin or carbamazepine vs normal controls. Results. - Addition of phenytoin or carbamazepine to normal human serum in vitro resulted in a significant increase in free [T.sub.4] fraction and free [T.sub.4] (P < .001). In patients taking phenytoin or carbamazepine, serum total [T.sub.4] decreased significantly to 60% and 74%, respectively, of the control serum concentration (P < .001 for both phenytoin and carbamazepine); free [T.sub.4] fraction (by ultrafiltration assay) increased 65% and 44%, respectively (P < .001 for phenytoin, P < .01 for carbamazepine); and free [T.sub.4] remained unchanged. Free [T.sub.4] concentration measured by a commercial kit (1:5 serum dilution) was significantly lower than the control concentration in both phenytoin- and carbamazepine-treated patents. Serum free [T.sub.3] and serum TSH were also normal in phenytoin- and carbamazepine-treated patients. Conclusions. - Therapeutic levels of phenytoin and carbamazepine displace [T.sub.4] and [T.sub.3] from serum binding proteins. When added to serum, the drugs effect an increase in free hormone fractions and free [T.sub.4] and [T.sub.3]. In drug-treated patients, increased free [T.sub.4] and free [T.sub.3] fractions offset the significant decrease in serum [T.sub.4] and [T.sub.3], resulting in normal free [T.sub.4] and free [T.sub.3] concentrations. Since currently available clinical tests will continue to show decreased free [T.sub.3] concentrations in patients taking phenytoin or carbamazepine, clinicians should rely on serum TSH measurements to confirm the euthyroid status of these patients.

The native plasmid of Pseudomonas sp. strain NS671, pHN671, contains genes required for the conversion of 5-substituted hydantoins to the corresponding L-amino acids. Previous analyses have identified genes hyuA and hyuB as involved in this conversion process. Plasmid pHPB12, a derivative of pHN671, was further analyzed to isolate additional genes involved in hydantoin racemization. The analysis identified an additional gene, designated hyuE, as involved in this process. The proposed identity of the hyuE gene product is a hydantoin racemase.

Anxiety is a fundamental aspect of the human experience. It can be an adaptive response to a perceived threat, with both psychological and physiological features. In the short term, anxiety [...]

Byline: George. Koshy, Ron. Varghese, Dukhabandhu. Naik, Hesargatta. Asha, Nihal. Thomas, Mandalam. Seshadri, Mathew. Alexander, Maya. Thomas, Sanjith. Aaron, Thomas. Paul Background: Although there are reports describing the association of [...]

Byline: Pooja. Harijan, Arif. Khan, Nahin. Hussain Children and adolescents treated with antiepileptic drugs are known to have problems with bone metabolism, bone mineral density loss, and 2-3 times the [...]

Psychiatrists are often asked to medicate patients with chronic kidney disease (CKD). Currently, there are 350,000 Americans who receive maintenance dialysis for renal failure, and this predominantly elderly population with [...]

Epileptic syndromes have very diverse primary causes, which may be genetic, developmental or acquired. In rodent models, altering glutamate receptor or glutamate transporter expression by knockout or knockdown procedures can induce or suppress epileptic seizures. Regardless of the primary cause, synaptically released glutamate acting on ionotropic and metabotropic receptors appears to play a major role in the initiation and spread of seizure activity. In rodent models of acquired epilepsy and in human temporal lobe epilepsy, there is evidence for enhanced functional efficacy of ionotropic N-methyl-D-aspartate (NMDA) and metabotropic (Group I) receptors. In animal models of epilepsy, antagonists acting at NMDA receptors or at Group I metabotropic receptors have potent anticonvulsant actions. J. Nutr. 130: 1043S-1045S, 2000. KEY WORDS: * epilepsy * glutamate * N-methyl-D-aspartate * kindling * glutamate metabotropic receptors * antiepileptics

The development of tolerance is an important factor determining the clinical usefulness of drugs that need to be used chronically. This is the case for essential tremor, or tremor for which no immediate cause can be assigned. The drug primidone, which is metabolically converted to phenobarbital in the body, may be prescribed for essential tremor, and often the effect of the first dose of primidone is far more impressive than the response to propranolol, another commonly used tremorolytic (tremor-reducing) drug. However, there is some indication that tolerance to these agents, as evidenced by decreasing effectiveness and the return of tremor, may occur to a greater degree with primidone. The authors present the case of a 61-year-old man in whom tolerance developed after one dose of primidone. The patient had a 12-year history of essential tremor. His condition responded to propranolol, but not to ethanol. The patient had discontinued use of propranolol due to the development of bradycardia, or slowing of the heartbeat. The first dose of primidone resulted in noticeable improvement in tremor within one hour, followed by virtual disappearance of the tremor by three hours. The tremor was still gone after one day, but had returned 48 hours after the first dose. After the second dose, there was little or no improvement in the tremor, and the patient developed side effects including malaise, nausea, confusion, and ataxia (poor coordination). These effects were sufficiently unpleasant that the patient declined any further treatment with the compound. While primidone usually continues to be effective, there have been reports that effectiveness may be lost over a period of several months in some patients. The present case is remarkable for the rapidity with which the drug's effectiveness disappeared. Another striking feature of the case is that the tolerance which developed for the tremor-suppressing effects of the drug did not affect the development of side effects. This suggests that the pharmacologic and physiologic mechanisms responsible for the tremorolytic effect of primidone are distinct from those responsible for the sedation and confusion associated with the drug. (Consumer Summary produced by Reliance Medical Information, Inc.)

A research study by Dikmen and colleagues in the March 13, 1991 issue of The Journal of the American Medical Association reports negative effects on cognitive function of phenytoin, an anticonvulsant drug. Subjects with head injuries received either phenytoin (often prescribed in such cases to prevent seizures) or a placebo (inactive) drug for 12 months and underwent neurobehavioral testing 1, 12, and 24 months after injury. Those who had received phenytoin performed more poorly on several tests than those who had received the placebo, indicating that prophylactic use of at least this anticonvulsant after head injury should be questioned. Evidence is cited from other studies that attempted to evaluate the effects of such drugs on healthy volunteers and on animals; in general, the drugs reduce cognitive performance. It appears that newer anticonvulsant drugs, such as carbamazepine and valproate sodium, have fewer adverse effects on cognition than older medications such as phenytoin and phenobarbital. At the same time, anticonvulsants may have positive effects as psychotropic drugs (for treating psychiatric disorders). More research is needed to determine the effects of these drugs on conditions not associated with epilepsy or seizures; with such information, better decisions can be made concerning their use in seizure patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Animal studies have shown that prenatal exposure to the anticonvulsant drugs phenobarbital and phenytoin alters steroid hormone levels which consequently leads to disturbed sexual differentiation. In this study, possible sequelae of prenatal exposure to these anticonvulsants on gender development in humans were investigated. A follow-up study was carried out in phenobarbital- and phenytoin-exposed subjects and control subjects matched for age, sex, and the mothers' ages. Subjects were born in the Academic Medical Center between 1957 and 1972. Out of 243 exposed and 222 control subjects who were asked to volunteer, 147 exposed subjects (72 male, 75 female) and equal numbers of their matched control subjects participated in the follow-up study. They were interviewed and were asked to fill out questionnaires on gender role behavior, gender development, and sexual orientation. As a group, exposed and control subjects did not differ with respect to gender role behavior, although higher numbers of prenatally anticonvulsant-exposed subjects reported current or past cross-gender behavior and/or gender dysphoria. Three prenatally anticonvulsant-exposed subjects were transsexuals and had undergone sex reassignment surgery, a remarkably high rate given the rarity of transsexualism. In addition, two exposed males had exclusively homosexual experiences, whereas none of the control males reported exclusive homosexual behavior. The groups did not differ in attainment of pubertal psychosexual milestones. KEY WORDS: prenatal exposure-delayed effects; phenobarbital; phenytoin; gender identity disorder; psychosexual development.